RRC ID 51640
Author Maeda Y, Echizen K, Oshima H, Yu L, Sakulsak N, Hirose O, Yamada Y, Taniguchi T, Jenkins BJ, Saya H, Oshima M.
Title Myeloid Differentiation Factor 88 Signaling in Bone Marrow-Derived Cells Promotes Gastric Tumorigenesis by Generation of Inflammatory Microenvironment.
Journal Cancer Prev Res (Phila)
Abstract It has been established that COX-2 and downstream signaling by prostaglandin E2 (PGE2) play a key role in tumorigenesis through generation of inflammatory microenvironment. Toll-like receptor (TLR) signaling through myeloid differentiation factor 88 (MyD88) also regulates inflammatory responses in tumors. However, the relationship between these distinct pathways in tumorigenesis is not yet fully understood. We herein investigated the role of MyD88 in gastric tumorigenesis using Gan mice, which develop inflammation-associated gastric tumors due to the simultaneous activation of the COX-2/PGE2 pathway and Wnt signaling. Notably, the disruption of Myd88 in Gan mice resulted in the significant suppression of gastric tumorigenesis with the inhibition of inflammatory responses, even though COX-2/PGE2 pathway is constitutively activated. Moreover, Myd88 disruption in bone marrow-derived cells (BMDCs) in Gan mice also suppressed inflammation and tumorigenesis, indicating that MyD88 signaling in BMDCs regulates the inflammatory microenvironment. We also found that expression of Tlr2 and its coreceptor Cd14 was induced in tumor epithelial cells in Gan mice, which was suppressed by the disruption of Myd88. It has already been shown that TLR2/CD14 signaling is important for stemness of intestinal epithelial cells. These results indicate that MyD88 in BMDCs, together with COX-2/PGE2 pathway, plays an essential role in the generation of the inflammatory microenvironment, which may promote tumorigenesis through induction of TLR2/CD14 pathway in tumor epithelial cells. These results suggest that inhibition of TLR/MyD88 signaling together with COX-2/PGE2 pathway will be an effective preventive strategy for gastric cancer.
Volume 9(3)
Pages 253-63
Published 2016-3-1
DOI 10.1158/1940-6207.CAPR-15-0315
PII 1940-6207.CAPR-15-0315
PMID 26888865
MeSH Animals Apoptosis Blotting, Western Bone Marrow / metabolism Bone Marrow / pathology* Bone Marrow Transplantation Cell Proliferation Cell Transformation, Neoplastic / immunology Cell Transformation, Neoplastic / metabolism Cell Transformation, Neoplastic / pathology* Cyclooxygenase 2 / metabolism Dinoprostone / metabolism Humans Immunoenzyme Techniques Inflammation / immunology Inflammation / metabolism Inflammation / pathology* Mice Mice, Knockout Myeloid Differentiation Factor 88 / physiology* Precancerous Conditions / immunology Precancerous Conditions / metabolism Precancerous Conditions / pathology* RNA, Messenger / genetics Real-Time Polymerase Chain Reaction Reverse Transcriptase Polymerase Chain Reaction Signal Transduction Stomach Neoplasms / immunology Stomach Neoplasms / metabolism Stomach Neoplasms / pathology* Toll-Like Receptor 2 / metabolism Tumor Burden Tumor Cells, Cultured
IF 3.473
Times Cited 17
Human and Animal Cells MKN74(RCB1002) RAW 264(RCB0535)